Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for two polymorphs of the drug tolbutamide: FI H and FV. Heat capacities have been determined by temperature-modulated DSC for four polymorphs: FI L , FI H , FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI H through a thermodynamic cycle. Calorimetric data has been used to derive a quantitative polymorphic stability relationship between these four polymorphs, showing that FII is the stable polymorph below approx. 333 K, above which temperature FI H is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI L and FI H has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in five pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile and toluene) over the temperature range 278 K -323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the five solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are non-linear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data has been correlated and extrapolated to the melting point using a semiempirical regression model.

In this work the influence of temperature and composition on the activity coefficient in solution has been investigated, based on isothermal and isobaric vapor–liquid equilibrium data for 30 binary systems classified into four groups: water–organic, polar–polar, polar–nonpolar, and nonpolar–nonpolar systems. It is shown that under most conditions the temperature dependence of the activity coefficient is clearly weaker than the composition dependence. The analysis is extended to include solid–liquid solubility data of 15 binary systems of relatively large and complex organic molecules in organic solvents. Based on this, a novel approach to estimate the thermodynamic driving force of crystallization from solution is proposed. Rather than assuming that the activity coefficient ratio equals unity, it is shown that in most cases a more accurate assumption is to neglect only the temperature dependence of the activity coefficient. This allows the activity coefficient ratio to be estimated from solid–liquid equilibrium data.

In this work, the NRTL-SAC and the Pharma UNIFAC models are evaluated with respect to the capability of prediction of solid-liquid equilibria of pharmaceutical compounds in organic solvents. The original NRTL-SAC model is extended through the introduction of temperaturedependent binary interaction parameters, and the two versions of the model are parametrized using VLE data. The performance of the NRTL-SAC models for correlation and prediction of the temperature-dependent forms of the NRTL-SAC model (29 systems) are 1.64, 1.17 and 1.09, respectively. Comparing only those systems for which all models were evaluated (18 systems), the RMSLE values are 1.42, 1.06 and 0.87, respectively.

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